In the mammalian eye, macular degeneration (also called age related macular degeneration, AMD) is a pathological condition that is the most common cause of legal blindness among individuals over the age of 60, with an incidence ranging from 11% to 18.5% in individuals over the age of 85. In the United States, AMD affects roughly 3.6 million individuals, with over 200,000 new cases developing annually.
One type of AMD results in proliferation of new blood vessels in the subretinal area, typically the choroid. In the normal retina, both the large blood vessels and the capillaries have intact vessel walls. In the normal choroid, the large vessels have intact vessel walls, but the capillaries have fenestrations or openings in their walls. In patients with AMD, new blood vessels proliferate from the choriocapillaries through defects in Bruch's membrane beneath or on top of retinal pigment epithelium (RPE), and form vascular membranes. The resulting choroidal neovascularizations (new vessels in the choroid) occur in about 8-10% of all patients with AMD, and are also seen in patients with pathologic myopia and presumed ocular histoplasmosis syndrome, as well as other idiopathic conditions.
While the presence of the new vessels themselves is not problematic, any endogenous or exogenous fluid contained in these vessels (for example, blood, serous fluid, solubilized drug, etc.) will leak outside of the vessels and into the surrounding spaces. This accumulation of fluid can result in serous and hemorrhagic detachment of the RPE and neurosensory retina, and can lead to scarring in this area (fibrous deform scarring), resulting in decreased vision or even loss of vision. Thus, it is the fluid leakage from these new vessels in this type of AMD, called neovascular, exudative, or occult AMD, that is the cause of the resulting visual impairment.
Another type of AMD occurs less commonly and is due to dead RPE cells; this is termed atrophic AMD. In either type of AMD, without treatment, many of the affected individuals will become legally blind.
Patients with an early stage of AMD can be diagnosed in an examination by the presence of abnormal clumps of pigments in the eye. Accumulated dead outer segments of photoreceptor cells under the RPE is termed drusen. Hyaline excrescences that are located in Bruch's membrane (lamina basalis choroidea) also form. The presence of large, soft drusen in the eye indicates a pre-stage of exudative AMD, and places patients at higher-than-average risk for developing neovascularizations, especially if one eye is already affected.
To date, there are no known specific measures to prevent the occurrence of AMD. Nutritional therapies using antioxidants and zinc have been tried. There is one report (Ophthalmology 105:11-23, 1998) of a clinical trial using lasers to prophylactically treat patients showing abnormal pigment in both eyes (bilateral drusen).
For patients already diagnosed with AMD in one or both eyes, treatment involves targeting light (phototherapy) to the macular area containing the nascent defective blood vessels to inhibit or impair their function. One type of phototherapy is photodynamic therapy (PDT). In PDT, a photosensitive agent is administered into the vessels of a patient, then the agent is activated at the target site of the new vessels (the macula) by directing low energy light from a laser specifically to this area. The activated agent generates free radicals and other activated chemical species which destabilize and destroy the new vessels.
PDT has been reported to be of some benefit to patients having AMD. For example, one study (Arch. Ophthalmol. 17:1329-1345, 1999) evaluated PDT in four hundred and two eyes from patients diagnosed with AMD in at least one eye. Treatment outcome was assessed by comparing the patient's ability to accurately read a conventional vision chart (one having about five letters per line) pre-treatment and post-treatment. At twelve months post-PDT, 61% of the eyes (246/402) lost fewer than 15 letters (that is, the patient lost less than about three lines on a standard visual chart), while 46% of the eyes (96/207) from patients undergoing treatment with a placebo lost fewer than 15 letters (p<0.001). At twenty-four months post-PDT, the visual acuity and contrast sensitivity was sustained in patients receiving PDT. A significantly greater percentage of these patients (58%) lost fewer than 15 letters, compared to patients undergoing treatment with a placebo (38%). However, only 16% of the patients receiving PDT had improved vision, compared to 7% of the patients receiving a placebo.
Another type of phototherapy is photocoagulation therapy. In photocoagulation therapy, high energy light from a laser is directed specifically to the target site of the new vessels. The heat generated from the high energy laser coagulates the fluid in and around the new vessels. Laser photocoagulation is not a form of PDT; it is a separate treatment approach. It uses lateral transfer of heat, applied with a cautery-like method, to coagulate fluid within and surrounding the vessel, while PDT uses an activated photosensitive agent to generate active chemicals which damage or destroy the new vessels.
While either PDT or laser photocoagulation therapy is separately used to treat patients with AMD, neither is without drawbacks. A problem with PDT is that its effects are transient; patients receiving PDT must be retreated about every three months. Furthermore, the patients require at least five retreatments within the first two years merely to stabilize their condition, and before any therapeutic effect occurs. These cumulative treatments damage the retina, further reducing the patient's visual acuity.
One drawback of laser photocoagulation is that it is non-selective, and does not target only the new blood vessels. It must therefore be administered so that only the lesions are targeted, and the unaffected surrounding tissues are undamaged. However, in about half of the patients with AMD, the new vessels are located in the subfoveal area, which is difficult or impossible to target with laser coagulation without damaging the sensory retina. Another drawback is that photocoagulation treatment is not permanent and recurrence rates for new vessel production are high, reaching 39-76%, usually within the first two years. However, repeated treatments can actually induce the growth of new vessels and membranes (subretinal neovascular membranes and recurrent choroidal neovascularizations) at the site of the treatment. Repeated treatments may also irreversibly damage unaffected areas of the retina, including the neurosensory retina and RPE. Thus, the treatment itself may result in the patient having further reduced vision over a period of time. Specifically, some patients undergoing photocoagulation therapy develop scotoma, which is an area of depressed vision within the visual field, surrounded by an area of less depressed or of normal vision.
Methods to further refine the treatment of AMD to reduce or eliminate the above-described problems are therefore needed. Methods to prevent or delay the onset of AMD, and methods to maintain visual acuity and prevent further loss of vision in patients with AMD, are also needed.